Cancer is a debilitating disease that accounts for more than half a million deaths each year. There is a profound need for more effective, selective and safe treatments for cancer. Existing treatments for this pervasive, life threatening disease, such as chemotherapy and surgery, rarely eliminate all malignant cells, and often exhibit deleterious side-effects that can outweigh therapeutic benefit.
One approach that has the potential to address many of the shortcomings of current cancer treatments is oncolytic adenoviral therapy (Pesonen, S. et al., Molecular Pharmaceutics,. 8(1): p. 12-28 (2010)). These viruses are designed to replicate specifically in cancer cells, but leave normal cells unharmed. One way to engineer tumor selectivity is to target adenovirus infection to receptors upregulated on tumor cells, for example EGFR family members (Zhang H, Berezov A, Wang Q, Zhang G, Drebin J, Murali R, et al. ErbB receptors: from oncogenes to targeted cancer therapies. J Clin Invest. 2007; 117(8):2051-8. PMCID: 1934579), CEACAM (Li H J, Everts M, Pereboeva L, Komarova S, Idan A, Curiel D T, et al. Adenovirus tumor targeting and hepatic untargeting by a coxsackie/adenovirus receptor ectodomain anti-carcinoembryonic antigen bispecific adapter. Cancer Res. 2007; 67(11):5354-61), EpCAM (Haisma H J, Pinedo H M, Rijswijk A, der Meulen-Muileman I, Sosnowski B A, Ying W, et al. Tumor-specific gene transfer via an adenoviral vector targeted to the pan-carcinoma antigen EpCAM. Gene Ther. 1999; 6(8):1469-7), and HLA-A1/MAGE-A1 (de Vrij J, Uil T G, van den Hengel S K, Cramer S J, Koppers-Lalic D, Verweij M C, et al. Adenovirus targeting to HLA-A1/MAGE-A1-positive tumor cells by fusing a single-chain T-cell receptor with minor capsid protein IX. Gene Ther. 2008; 15(13):978-89). For a review of various strategies of adenovirus targeting, see Noureddini S C and Curiel D T (Genetic targeting strategies for adenovirus. Mol Pharm. 2005; 2(5):341-7; Nicklin S A, Wu E, Nemerow G R, Baker A H. The influence of adenovirus fiber structure and function on vector development for gene therapy. Mol Ther. 2005; 12(3):384-93).
Adenovirus (Ad) is a self-replicating biological machine. It consists of a linear double-stranded 36 kb DNA genome sheathed in a protein coat. Ad requires a human host cell to replicate. It invades and hijacks the cellular replicative machinery to reproduce and upon assembly induces lytic cell death to escape the cell and spread and invade surrounding cells (FIG. 1). No ab initio system has come close to mimicking the autonomy and efficiency of Ad, however, Applicants have developed new strategies to systematically manipulate the Ad genome to create novel adenoviruses. Henceforth, with the ability to manipulate the Ad genome, Applicants can take the virus by the horns and redesign it to perform the functions of tumor-specific infection, replication, and cell killing.
Currently, adenoviral vectors rely on a single cellular receptor for their uptake, which significantly limits their therapeutic potential. Ad5 infection is mediated primarily through interactions between the fiber protein on the outer viral capsid and the coxsackie and adenovirus receptor (CAR) on human epithelial cells. Unfortunately, many cancer cells do not express CAR, such as mesenchymal and deadly metastatic tumor cells. Since viral replication/killing is limited by the ability to infect cells, there is a need for viruses that infect tumor cells via receptors other than CAR, ideally those specifically upregulated on tumor cells. The present invention addresses these and other needs in the art by providing viral compositions and methods that chemically link viral capsids via chemical adapters to a broad variety of cellular receptors. Provided herein is a novel, inducible, genetically encoded chemical adapter system that retargets infection to multiple cell types, and is not lost upon viral replication. The compositions provided herein can be used to customize an oncolytic virus to target different cellular receptors over the course of infection.